Abstract
Disruption of the alveolar–capillary barrier and accumulation of pulmonary edema, if not resolved, result in poor alveolar gas exchange leading to hypoxia and hypercapnia, which are hallmarks of acute lung injury and the acute respiratory distress syndrome (ARDS). Alveolar fluid clearance (AFC) is a major function of the alveolar epithelium and is mediated by the concerted action of apically-located Na+ channels [epithelial Na+ channel (ENaC)] and the basolateral Na,K-ATPase driving vectorial Na+ transport. Importantly, those patients with ARDS who cannot clear alveolar edema efficiently have worse outcomes. While hypoxia can be improved in most cases by O2 supplementation and mechanical ventilation, the use of lung protective ventilation settings can lead to further CO2 retention. Whether the increase in CO2 concentrations has deleterious or beneficial effects have been a topic of significant controversy. Of note, both low O2 and elevated CO2 levels are sensed by the alveolar epithelium and by distinct and specific molecular mechanisms impair the function of the Na,K-ATPase and ENaC thereby inhibiting AFC and leading to persistence of alveolar edema. This review discusses recent discoveries on the sensing and signaling events initiated by hypoxia and hypercapnia and the relevance of these results in identification of potential novel therapeutic targets in the treatment of ARDS.
Highlights
ROLE OF HYPOXIA IN INFLAMMATION AND ALVEOLAR FLUID BALANCE IN acute lung injury (ALI)Adaptation to hypoxia is critically important for cellular survival as oxygen is required for ATP synthesis in the mitochondria by oxidative phosphorylation [8]
Reviewed by: John McGuire, University of Washington, United States Juerg Hamacher, Lindenhof Hospital, Switzerland Michael Anthony Matthay, University of California, San Francisco, United States
Both low O2 and elevated CO2 levels are sensed by the alveolar epithelium and by distinct and specific molecular mechanisms impair the function of the Na,K-ATPase and epithelial Na+ channel (ENaC) thereby inhibiting Alveolar fluid clearance (AFC) and leading to persistence of alveolar edema
Summary
Adaptation to hypoxia is critically important for cellular survival as oxygen is required for ATP synthesis in the mitochondria by oxidative phosphorylation [8]. Severe hypoxia leads to rapid (within minutes) endocytosis of the Na,K-ATPase molecules from the plasma membrane (PM) into intracellular pools, thereby decreasing activity of the enzyme [15] It appears that in the first hour of hypoxic exposure this trafficking event is solely responsible for the hypoxia-induced impairment of Na,K-ATPase function as the total cellular abundance of the transporter remains unchanged, excluding the possibility of accelerated degradation of the transporter upon short-term hypoxia. Considering that the Na,K-ATPase accounts for a significant proportion of the energy expenditure of cells, as mentioned above, it appears logical that as an adaptive mechanism to hypoxia the active Na,K-ATPase molecules (located at the PM) will be removed from the surface and degraded more rapidly than degradation of the inactive molecules (located in the intracellular pools) occurs to reduce cellular energy consumption and promote survival [8]. A marked reduction in the amiloride-sensitive apical Na+ current upon hypoxia can be fully prevented by inhibition of the proteasome and by the ROS scavenger N-acetyl-cysteine [31], suggesting that the ubiquitin– proteasome system is critically required for the hypoxia-driven down-regulation of ENaC and further confirming the central role of ROS in the hypoxic impairment of alveolar epithelial Na+ transport processes
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